The goal of this research is to study with physiological techniques the functional alterations that accompany the microvascular disease in experimental diabetes mellitus. The permeability of capillaries to plasma albumin will be quantitatively determined by measuring the PS (permeability times surface area) product in the heart, the hind limb and the kidney for the peritubular capillaries, and determining the TER (transcapillary escape rate) for the whole body. Streptozotocin will be administered as the diabetogenic agent to rats, and littermate controls will be studied together with the experimental animals. In earlier studies it was demonstrated that certain definite functional alterations are detectable in the diabetic animals; in this project further studies will be carried out at earlier times. The effects of diet, therapeutic insulin treatment, steady or oscillating blood sugar levels, etc. on the development of microangiopathy in experimental diabetes will also be investigated. The morphology of capillaries in these animals will also be studied in a collaborative arrangement by light and electronmicroscopy. An additional goal of this project is to investigate the apolipoprotein composition of plasma and lymph in experimental diabetes. This study, to be carried out in collaboration with Dr. P. S. Roheim of the Albert Einstein Medical College, arose from two previous observations made by us: 1. We obtained evidence to show that apolipoproteins, protein molecules of relatively small size which are for the most part associated with lipids in the circulating blood plasma, are also present in lipid free form and as such pass through the capillary membrane into the lymph. 2. In experimental diabetes the lipoprotein and apolipoprotein composition of the plasma show drastic alterations. In the forthcoming years we will study the kinetics of passage of apolipoproteins from plasma to lymph, and the penetration of apolipoproteins across the endothelium of large blood vessels into the media of wall.